Phenylpiperazinylalkyl esters



United States Patent "ice 3,038,901 PHENYLPIPERAZINYLALKYL ESTERS ShinHayao, Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart,Ind., a corporation of Indiana No Drawing. Filed Mar. 17, 1960, Ser. No.15,525 6 Claims. (Cl. 260-268) This invention relates to new and usefulcompositions of matter and particularly to phenylpiperazinylalkyl esterswhich possess sedative activity and are useful in alleviations ofnervous tension and anxiety.

More specifically, the new compounds may be designated asw-(l-phenyl-4-piperazinyl)alkyl benzoates and represented by thefollowing structural formula:

wherein R may be hydrogen, halogen, preferably chlorine, or a methoxygroup; C H stands for a straight or branched alkylene chain with n beingat least 1 and at most and Ar represents 4-methoxyphenyl,3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl or 3,4,5-trimethoxyphenyl.The novel compounds of this invention have utility as physiologicallyactive agents; they possess sedative properties similar to, and improvedover, those of reserpine, being constituted in part of the activeportion of the reserpine molecule, namely, the 3,4,5-trimethoxybenzoylmoiety, or of other similar benzoyl moities, and a 1,4- disubstitutedpiperazinyl moiety, characterized by its central depressant activity andadrenergic blocking action.

Above defined compounds wherein R is hydrogen or halogen can be preparedby reacting l-phenyl-piperazine or l-p-halophenylpiperazine with anappropriate haloalkanol to produce al-phenyl-4-(w-hydroxyalkyl)piperazine or 1p-halophenyl4-(w-hydroxyalkyl)piperazine and reacting these intermediatepiperazines with mono-, dior tri-substituted benzoyl chlorides to obtainthe desired phenylpiperazinylalkyl benzoates.

The mode of formation may be graphically presented by the followingequation:

STEP 1 STEP 2 wherein C H and Ar have the meanings ascribed to themabove, R is hydrogen or halogen and X is also halogen.

Moreover, it has been found that some compounds of this class can alsobe prepared by reacting the phenylpiperazine with a lower alkyleneoxide, such as ethylene oxide or propylene oxide, as illustrated byExamples III and IV.

To obtain a compound wherein a methoxy radical is the R substituent inthe para-position of the terminal phenyl portion of the defined alkylester, p-anisidine, eth ylene oxide and thionyl chloride are employed asstarting materials. The consequent reaction product, N,N'bis-(2-chloroethyl)-p-anisidine, is in turn reacted with an amino alkanol toproduce the intermediate 1-p-rnethoxyphenyl-4-(w-hydroxyalkyl)piperazine, which is then esterified as indicated above.These reactions are carried out according to the following diagrammaticpresentation:

weasel Patented June 12, 1962 STEP 1 STEP 2 CHaCHaOl CHzCHaCl STEP 3wherein C H and Ar have the meanings given to them above.

The present compounds may be obtained as free bases having the formulagiven above or preferably, for pharmacological use, as non-toxic,water-soluble addition salts of halogen acids, sulfuric acid, maleicacid, and the like.

These new compounds and the methods for their preparation may beexemplified more specifically by the following illustrative examples:

Example I 4-(1-phenyl-4-pipemzinyl) butyl 3,4,5 -trimethoxyben z oatedihydrochl0ride.1-phenyl-4-(4-hydroxybutyl)piperazine was prepared in23.7% yield from 0.2 mole each of 4-chlorobutanol and l-phenylpiperazinein boiling ethanol in presence of anhydrous sodium carbonate. Unreactedamine was recovered in 33% yield. To a solution of1-phenyl-4-(4-hydroxybutyl)piperazine (0.046 mole) in 150 ml. of benzenewas added equimolar metallic sodium. To this milky solution was addeddropwise a solution of 3,4,5-trimethoxybenzoyl chloride in ml. ofbenzene. It was refluxed for an hour, washed with water and dried. Thebenzene solution was added to methanolic hydrogen chloride and boileddown with ethyl acetate until a crystalline solid separated. On cooling,the product was collected by suction, yield 18.3 g. (79.5%), MP. 199200(d.). (Temperature degrees are given in centigrades.) A sample wasrecrystallized twice from methanol-ethyl acetate to give a colorlesspowder of MP. 202 (d.).

Anal.Calcd for C H N O '2HCl: N, 14.57. Found: N, 5.68; HCl, 14.91.

PHARMACOLOGY The acute median lethal dose (A-LDSO) for oraladministration to rats of this compound is 2,480 mg./kg. The acutemedian sedative dose (A-SDSO) is 4.16% of the A-LDSO in the first hourand 4.24% of the A-LDSO in the third hour.

Up to 1,350 mg./kg., a chiclolike posture, characteristic of reserpine,was seen in the first five hours after administration. N0 convulsions orhypnosis were observed before death dose.

A special sedation test demonstrated that at 9% of the A-LDSO four outof five rats, and at 20%, five out of five rats were sedated one hourafter oral administration of the compound.

A motor relaxation screening showed that at 9% of the A-LDSO one out offive rats, and at 20%, five out of five rats were unable to walk on arotor-rod one hour after its oral administration.

By a convulsive facilitation test the potential utility of this compoundin the treatment of schizophrenia was demonstrated in that at 9% of theA-LDSO two out of five rats, at 13% and 20%, four out of five rats hadconvulsions at a minimum voltage one hour after its oral administration.

The above compound also possesses adrenergic blocking action shown invivo in the following way: An intravenous dose of 8 mg./ kg. in ananesthetized dog blocked and reversed the vasodepressor effect ofinjected epinephrine and partially blocked the effect of preganglioniccervical sympathetic stimulation on the pupil and nictitating membrane.The nictitating membrane response to injected epinephrine was alsodestroyed. A vasodepressor activity was observed at the same time withthe compound producing a sustained fall in blood pressure.

Unlike reserpine the above compound had no cumulative effect.

Example 11 3-(1-phenyl-4-piperazinyl)propyl 3,4,5-trimethoxybenzoatedihydrchloride.-l-phenylpiperazine (31.6 g., 0.2 mole) was alkylatedwith 3-bromopropanol (27. 8 g., 0.2 mole) in 100 ml. of absolute ethanolin the presence of 15 g. of anhydrous sodium carbonate during 3 hoursunder reflux. The salt was removed, and the filtrate was freed fromsolvent leaving a syrup which was dissolved in dilute hydrochloric acid,heated with Norit, filtered and made alkaline with aqueous sodiumhydroxide to give a sandy solid of M.P. 8693, yield 36.8 g. (83.5%). Asample was once recrystallized from aqueous methanol to give a colorlesspowder melting at 83-84.

Anal.Calcd for C13H2QN20: N, 12.7. Found: N, 12.9.

To a solution of 1-phenyl-4-(3-hydroxypropyl)piper-azine (22.2 g., 0.1mole) in 100 ml. of chloroform was added a solution, in 100 ml. ofchloroform, of a crude 3,4,5-trimethoxybenzoyl chloride prepared from3,4,5- trir'nethoxybenzoic acid (21.2 g., 0.1 mole) and 50 ml. ofthionyl chloride. The reaction mixture was refluxed for 3 hours and thesolvent was removed in vacuo to give a syrup, which was taken up inmethanol, saturated with dry hydrogen chloride and boiled down withethyl acetate to give a colorless solid of M.P. 182-184 (d.), yield 23.9g. A sample was once recrystallized from methanol-ethyl acetate to givea pure product melting at ISO-181 (d.).

Anal.Calcd for C H N O -2HCl: N, 5.75. Found: N, 5.62 (Kjeldahl).

PHARMACOLOGY The A-LDSO of this compound is 2480 mg./kg. No convulsionsand hypnosis were observed at sublethal doses.

The sedation test demonstrated that at 20% of the A-LDSO five out offive rats were sedated, one as well as three hours after oraladministration.

The motor contro screening showed that at 20% of the A-LD50 five out offive rats were unable to walk on a rotor-rod one as well as three hoursafter administration.

By the convulsive facilitation test it was revealed that at 20% threeout of, five after one hour and none out of five after three hours hadconvulsions at minimum voltage.

Example III 2-(1-phenyl-4 piperazinyl) ethyl 3,4,5-trimethoxybenzoatedihydrocltlorz'de.--1 phenyl-4-(2 hydroxyethyl)- piperazine was preparedfrom l-phenylpiperazine and ethylene oxide in hot methanol in 64.5%yield. One recrystallization from benzene-Skelly B gave a pure aminoalcohol of 8485. One tenth molar solution of1-phenyl-4-(2-hydroxyethyl)-piperazine and 3,4,5trimethoxybenzoylchloride in 100 ml. of chloroform was refluxed for three hours. Thesolvent was removed in vacuo, and the residue was taken up in methanol,saturated With dry hydrogen chloride and diluted with ethyl acetatewhile hot to separate 38.6 g. (88.5%) of the product melting at185-189". It was recrystallized 4 twice from methanol-ethyl acetate togive a pure product of M.P. 188-190".

Anal.--Calcd for C H N O -2HCl: N, 5.92; HCl, 15.43. Found: N, 5.93;HCl, 15.31.

PHARMACOLOGY The A-LD50 of this compound is 2480 mg./kg. No convulsionswere noted for doses up to 122% of the A-LDSO. The hypnotic dose 50(HD50) is 66% of the A-LDSO.

A special sedation test showed that at 20% of the A-LDSO five out offive animals were sedated one and three hours after oral administration.

A motor relaxation test demonstrated that at 20% of the A-LD50 five outof five rats were unable to walk on a rotor-rod one as well as threehours after administration.

The convulsive facilitation test revealed that at 20% of the A-LDSO onehour after administration four out of five rats, and three hours afteradministration none out of five rats had convulsions at a minimumvoltage.

Example IV I-methyl 2-(1-phenyl-4 piperazinyl) ethyl 3,4,5trimethoxybenzoate dihydrochloride.-1 phenyl-4-(2hydroxypropyl)piperazine was prepared in 83% yield from1-phenylpiperazine and propylene oxide in hot methanol, M.P. 7678. Onetenth molar mixture of 1-phenyl-4-' (2-hydroxypropyl)piperazine and3,4,5-trimethoxybenzoyl chloride in ml. of chloroform was refluxed for 5hours. The solvent was removed in vacuo and the remaining semi-solid wastaken up in methanol, treated with dry hydrogen chloride and boiled downwith ethyl acetate until a crystalline solid separated, yield 38.5 g.(85.5%), M.P. 197-199. Two recrystallizations from methanol-ethylacetate gave 32.6 g. of pure product melting at 202-204 (d.).

Anal--C31Cd for C23H30N2052HC11 N, 14.99. Found: N, 5.85; HCl, 15.13.

PHARMACOLOGY The A-LDSO of this compound is 1655 mg/kg. The convulsivedose (CD50) is 72% of the A-LD50.

The sedation test showed that at 20% of the A-LD50 one hour afteradministration three out of five and after three hours four out of fiverats were unable to walk on a rotor-rod.

The convulsive facilitation test demonstrated that at 20% of the A-LD50none of five animals had convulsions at a minimum voltage one hour aswell as three hours after oral administration.

Example V 2-(] -p-meth0xyphenyl 4 piperazinyDethyl 3,4,5trimethoxybenzoate dihydr0chloride.-p-Anisidine (425 g., 3.45 mole) in450 ml. of methanol was treated with ethylene oxide for 8 hours at itsboiling point. The solvent was removed in vacuo to leave a solid mass ofM.P. 68-72. It was dissolved in 750 ml. of chloroform, cooled in anice-water bath and saturated with dry hydrogen chloride. Then 900 g.(7.55 mole) of thionyl chloride was added dropwise during 4 hours tomaintain gentle reflux and stirred at room temperature for 20 hours. Thesolvent and excess thionyl chloride was re moved in vacuo to give a darksolid mass which was dis methoxyphenyl-4-(2-hydroxyethyl)piperazine,M.P. 88 89". One recrystallization from benzene-Skelly B gave 38.5 g. ofthe pure product melting at 92-93".

Andl.-Oalcd for C H N O N, 5.93 (basic N). Found: N, 5.86.

A solution of the amino alcohol (23.6 g., 0.1 mole) and3,4,5trimethoxybenzoyl chloride (23.1 g., 0.1 mole) in 150 ml. ofchloroform was refluxed for an hour, the solvent was removed in vacuoand the residue was dissolved in methanol. It was treated with dryhydrogen chloride and diluted with ethyl acetate while hot to give 42.2g. (84%) of the product, M.P. 199-201 (softening at 190). It was oncerecrystallized from aqueous methanol-ethyl acetate to give colorlesscrystals of M.P. 205-206 (d.), yield 30.0 g.

Anal.Calcd for C23H30N2D6'2HC1I Found: HCl, 14.5. Example VI3-(1-p-chlorophenyl 4 pip'erazinyDpropyl 3,4,5 trimethoxybenzoatedihydrchloride.1p-chlorophenyl 4- (3-hydroxypropyl)piperazine wasprepared in 89% yield from 0.1 mole of each of 3bromo-1-propanol and1-pchlorophenylpiperazine in boiling ethanol in the presence ofanhydrous sodium carbonate. A solution of the thusobtained piperazine(11.1 g., 0.044 mole) and 3,4,5-trimethoxybenzoyl chloride (10.4 g.,0.044 mole) in 100 ml. of chloroform was refluxed for an hour to give agelatinous mixture. The solvent was removed in vacuo and the residue wasdissolved in 100 ml. of hot methanol, saturated with dry hydrogenchloride and ethyl acetate was added to separate a colorless solid. *Itwas collected by suction and dried in a vacuum desiccator. It wasrecrystallized once from hot methanol to give colorless sandy crystalsof M.P. l87-188 (d.), yield 11.4 g. (50.3%).

AVMZIr-CfilCd for C23H31C13N205I 14.0. Found: HCl, 13.8.

In accordance with the methods described in greater detail in the aboveexamples, the following compounds within the general formula were alsomanufactured:

Example VII 3-(1-p-methoxyphenyl-4 piperazinyDpropyl3,4,5-trimethoxybenzoate dihydrochloride.--M.P. 203-204".

Anal.-Calcd 01 C24H34C12N206: Found: Example VIII2-(1-p-chlorophenyl-4-piperazinyl)ethyl 3,4,5-trimethoxybenzoatedihydr0chl0ride.--M.P. l94194.5.

AnaL-Calcd for C H Cl N O HCl, 14.4. Found: HCl, 14.4. Example IX4-(1-phenyl 4-piperazinyl) bulyl 3,4 dimethoxy benzoatedihydrochl0ride.M.P. 184-1S5.

Anal.Calcd for C H Cl N O HCl, 15.5. Found: HCl, 15.8.

HCl, 14.5.

Example X 4-(1-phenyl-4-piperazinyl) butyl 3-meth0xybenz0atedihydr0chl0ride.-M.P. 210-211".

Anal.-Calcd for C H Cl N O HCl, 16.6. Found:

HC], 16.9. Example 4-(1-phenyl-4 piperazinyl)butyl 3,4methylenedioxybenzoate dihydrochloride.-M.P. 215218.

AnaL-Calcd for C H Cl N O 1161, 16.0. Found: HCI, 16.3.

Pharmaceutical compositions which are useful to induce sedation areconveniently and easily produced by combining a compound of the classhereinbefore described with fillers, carriers, extenders and/ orexcipients, such as are generally used in the preparation ofpharmaceutical products which are to be taken orally or givenparenterally. The compounds may be used in the form of the free base orof the salts of acids which are water-soluble and non-toxic, such as thehydrochloride, hydrobromide, sulfate and the like. The compositions maybe either in solid or liquid state and may be compounded as tablets,powders, capsules, suspensions and similar dosage forms, particularlyuseful for oral ingestion. In such form the composition may be preparedby mixing the foregoing compounds either in the form of a free base orthe Watersoluble non-toxic salts, with such common d-iluents ortabletting adjuncts as cellulose powder, cornstarch, lactose, talc,stearic acid, magnesium stearate, gums and the like, in accordance withconventional manufacturing practices common in the art.

Where the product is to be administered parenterally, the compounds,preferably in the form of their non-toxic water-soluble salts, may beassociated with such carriers as water, saline solution, glucosesolution and the like.

This application is a continuation-in-part of my application, SerialNumber 752,425, filed August 1, 1958, now abandoned.

What is claimed is:

1. A composition of matter selected from the group consisting ofphenylpiperazinylalkyl esters represented by the formula 2.4-(1-phenyl-4-piperazinyl)butyl 3,4,5 -trimethoxy- V benzoate.

3. B-(Lphenyl 4-piperazinyl)propyl 3,4,5-trimethoxybenzoate.

4. 2-(1-phenyl 4-piperazinyl)ethyl 3,4,5-trimethoxybenzoate.

5. 1-methyl-2-(1-phenyl-4 piperazinyl)ethyl 3,4,5-trimethoxybenzoate.

6. 2-(1-p-methoxyphenyl-4-piperazinyl)ethyl 3,4,5-trimethoxybenzoate.

References Cited in the file of this patent UNITED STATES PATENTSSchlitter Feb. 25, 1958 OTHER REFERENCES Chemical Abstracts, vol. 29,page 2959 (1935).

1. A COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OFPHENYLPIPERAZINYLALKYL ESTERS REPRESENTED BY THE FORMULA